ID FOLR2_HUMAN Reviewed; 255 AA. AC P14207; Q05CA5; Q6GTE8; DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 4. DT 02-SEP-2026, entry version 202. DE RecName: Full=Folate receptor beta; DE Short=FR-beta; DE AltName: Full=Folate receptor 2; DE AltName: Full=Folate receptor, fetal/placental; DE AltName: Full=Placental folate-binding protein; DE Short=FBP; DE Flags: Precursor; GN Name=FOLR2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=8445646; DOI=10.1006/jmbi.1993.1116; RA Page S.T., Owen W.C., Price K., Elwood P.C.; RT "Expression of the human placental folate receptor transcript is regulated RT in human tissues. Organization and full nucleotide sequence of the gene."; RL J. Mol. Biol. 229:1175-1183(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, TISSUE RP SPECIFICITY, GLYCOSYLATION, AND SUBCELLULAR LOCATION. RC TISSUE=Placenta; RX PubMed=2605182; DOI=10.1021/bi00446a042; RA Ratnam M., Marquardt H., Duhring J.L., Freisheim J.H.; RT "Homologous membrane folate binding proteins in human placenta: cloning and RT sequence of a cDNA."; RL Biochemistry 28:8249-8254(1989). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Placenta; RX PubMed=8106441; DOI=10.1016/s0021-9258(17)37605-6; RA Sadasivan E., Cedeno M.M., Rothenberg S.P.; RT "Characterization of the gene encoding a folate-binding protein expressed RT in human placenta. Identification of promoter activity in a G-rich SP1 site RT linked with the tandemly repeated GGAAG motif for the ets encoded GA- RT binding protein."; RL J. Biol. Chem. 269:4725-4735(1994). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pancreas, and Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 68-86; 102-120 AND 173-184. RX PubMed=2561247; DOI=10.1016/0065-2571(89)90091-5; RA Freisheim J.H., Price E.M., Ratnam M.; RT "Folate coenzyme and antifolate transport proteins in normal and neoplastic RT cells."; RL Adv. Enzyme Regul. 29:13-26(1989). RN [7] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=4066659; DOI=10.1016/s0021-9258(18)95679-6; RA Antony A.C., Kane M.A., Portillo R.M., Elwood P.C., Kolhouse J.F.; RT "Studies of the role of a particulate folate-binding protein in the uptake RT of 5-methyltetrahydrofolate by cultured human KB cells."; RL J. Biol. Chem. 260:14911-14917(1985). RN [8] RP GPI-ANCHOR AT ASN-230. RX PubMed=7578066; DOI=10.1021/bi00044a039; RA Yan W., Ratnam M.; RT "Preferred sites of glycosylphosphatidylinositol modification in folate RT receptors and constraints in the primary structure of the hydrophobic RT portion of the signal."; RL Biochemistry 34:14594-14600(1995). RN [9] RP PROTEOLYTIC PROCESSING. RX PubMed=9398177; DOI=10.1021/bi970845w; RA Wang J., Shen F., Yan W., Wu M., Ratnam M.; RT "Proteolysis of the carboxyl-terminal GPI signal independent of GPI RT modification as a mechanism for selective protein secretion."; RL Biochemistry 36:14583-14592(1997). RN [10] RP INDUCTION BY RETINOIC ACID. RX PubMed=20632143; DOI=10.1007/s13277-010-0074-0; RA Xu Y., Wang T., Tang R., Tang S.; RT "All-trans retinoic acid is capable of inducing folate receptor beta RT expression in KG-1 cells."; RL Tumor Biol. 31:589-595(2010). RN [11] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 24-228 IN COMPLEXES WITH FOLATE RP AND THE ANTIFOLATES METHOTREXATE; AMINOPTERIN AND PEMETREXED, FUNCTION, RP GLYCOSYLATION AT ASN-115 AND ASN-195, AND DISULFIDE BONDS. RX PubMed=23934049; DOI=10.1073/pnas.1308827110; RA Wibowo A.S., Singh M., Reeder K.M., Carter J.J., Kovach A.R., Meng W., RA Ratnam M., Zhang F., Dann C.E. III; RT "Structures of human folate receptors reveal biological trafficking states RT and diversity in folate and antifolate recognition."; RL Proc. Natl. Acad. Sci. U.S.A. 110:15180-15188(2013). RN [12] RP VARIANT [LARGE SCALE ANALYSIS] ASN-236. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Binds to folate and reduced folic acid derivatives and CC mediates delivery of 5-methyltetrahydrofolate and folate analogs into CC the interior of cells. Has high affinity for folate and folic acid CC analogs at neutral pH. Exposure to slightly acidic pH after receptor CC endocytosis triggers a conformation change that strongly reduces its CC affinity for folates and mediates their release. CC {ECO:0000269|PubMed:23934049, ECO:0000269|PubMed:2605182, CC ECO:0000269|PubMed:4066659}. CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Secreted CC {ECO:0000305}. CC -!- TISSUE SPECIFICITY: Expressed in placenta and hematopoietic cells. CC Expression is increased in malignant tissues. CC {ECO:0000269|PubMed:2605182, ECO:0000269|PubMed:8445646}. CC -!- INDUCTION: Up-regulated by retinoic acid. CC {ECO:0000269|PubMed:20632143}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:23934049, CC ECO:0000269|PubMed:2605182}. CC -!- SIMILARITY: Belongs to the folate receptor family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X69516; CAA49267.1; -; Genomic_DNA. DR EMBL; J02876; AAA35821.1; -; mRNA. DR EMBL; U02714; AAA17370.1; -; Genomic_DNA. DR EMBL; U02716; AAA17370.1; JOINED; Genomic_DNA. DR EMBL; AK222643; BAD96363.1; -; mRNA. DR EMBL; BC058036; AAH58036.1; -; mRNA. DR EMBL; BC027894; AAH27894.1; -; mRNA. DR CCDS; CCDS8212.1; -. DR PIR; A53315; A33417. DR RefSeq; NP_000794.3; NM_000803.5. DR RefSeq; NP_001107006.1; NM_001113534.2. DR RefSeq; NP_001107007.1; NM_001113535.2. DR RefSeq; NP_001107008.1; NM_001113536.2. DR RefSeq; XP_047282639.1; XM_047426683.1. DR RefSeq; XP_054224224.1; XM_054368249.1. DR PDB; 4KMY; X-ray; 1.80 A; A=24-228. DR PDB; 4KMZ; X-ray; 2.30 A; A=24-228. DR PDB; 4KN0; X-ray; 2.10 A; A=24-228. DR PDB; 4KN1; X-ray; 2.30 A; A=24-228. DR PDB; 4KN2; X-ray; 2.60 A; A/B/C=24-228. DR AlphaFoldDB; P14207; -. DR MDposit; P14207; -. DR SMR; P14207; -. DR BioGRID; 108633; 4. DR FunCoup; P14207; 263. DR IntAct; P14207; 1. DR NDEx; IQUERY-CP-FOLR2; 3 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000298223; -. DR BindingDB; P14207; -. DR ChEMBL; CHEMBL5064; -. DR DrugBank; DB00158; Folic acid. DR DrugBank; DB00563; Methotrexate. DR DrugBank; DB05168; Vintafolide. DR DrugCentral; P14207; -. DR GlyCosmos; P14207; 2 sites, No reported glycans. DR GlyGen; P14207; 4 sites. DR iPTMnet; P14207; -. DR PhosphoSitePlus; P14207; -. DR BioMuta; FOLR2; -. DR DMDM; 116241366; -. DR MassIVE; P14207; -. DR PaxDb; 9606-ENSP00000298223; -. DR PeptideAtlas; P14207; -. DR ProteomicsDB; 53031; -. DR ABCD; P14207; 4 sequenced antibodies. DR Antibodypedia; 30818; 360 antibodies from 34 providers. DR DNASU; 2350; -. DR Ensembl; ENST00000298223.11; ENSP00000298223.6; ENSG00000165457.16. DR Ensembl; ENST00000868542.1; ENSP00000538601.1; ENSG00000165457.16. DR Ensembl; ENST00000868543.1; ENSP00000538602.1; ENSG00000165457.16. DR Ensembl; ENST00000943224.1; ENSP00000613283.1; ENSG00000165457.16. DR Ensembl; ENST00000943228.1; ENSP00000613287.1; ENSG00000165457.16. DR GeneID; 2350; -. DR KEGG; hsa:2350; -. DR MANE-Select; ENST00000298223.11; ENSP00000298223.6; NM_000803.5; NP_000794.3. DR UCSC; uc001ose.5; human. DR AGR; HGNC:3793; -. DR ClinPGx; PA28209; -. DR CTD; 2350; -. DR DisGeNET; 2350; -. DR GeneCards; FOLR2; -. DR HGNC; HGNC:3793; FOLR2. DR HPA; ENSG00000165457; Tissue enhanced (placenta). DR MIM; 136425; gene. DR OpenTargets; ENSG00000165457; -. DR VEuPathDB; HostDB:ENSG00000165457; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT00950000183144; -. DR InParanoid; P14207; -. DR OMA; KDDFTCK; -. DR OrthoDB; 567542at2759; -. DR PAN-GO; P14207; 5 GO annotations based on evolutionary models. DR PhylomeDB; P14207; -. DR PathwayCommons; P14207; -. DR Reactome; R-HSA-163125; Post-translational modification: synthesis of GPI-anchored proteins. DR Reactome; R-HSA-196757; Metabolism of folate and pterines. DR Agora; ENSG00000165457; -. DR BioGRID-ORCS; 2350; 12 hits in 1153 CRISPR screens. DR ChiTaRS; FOLR2; human. DR EvolutionaryTrace; P14207; -. DR GeneWiki; FOLR2; -. DR GenomeRNAi; 2350; -. DR Pharos; P14207; Tchem. DR PRO; PR:P14207; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P14207; protein. DR Bgee; ENSG00000165457; Expressed in gall bladder and 182 other cell types or tissues. DR ExpressionAtlas; P14207; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0009897; C:external side of plasma membrane; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005542; F:folic acid binding; IDA:UniProtKB. DR GO; GO:0061714; F:folic acid receptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IBA:GO_Central. DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome. DR GO; GO:0015884; P:folic acid transport; IDA:UniProtKB. DR GO; GO:0006954; P:inflammatory response; NAS:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL. DR InterPro; IPR004269; Folate_rcpt. DR InterPro; IPR018143; Folate_rcpt-like. DR PANTHER; PTHR10517; FOLATE RECEPTOR; 1. DR PANTHER; PTHR10517:SF8; FOLATE RECEPTOR BETA; 1. DR Pfam; PF03024; Folate_rec; 1. DR PDBsum; 4KMY; -. DR PDBsum; 4KMZ; -. DR PDBsum; 4KN0; -. DR PDBsum; 4KN1; -. DR PDBsum; 4KN2; -. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Direct protein sequencing; Disulfide bond; KW Folate-binding; Glycoprotein; GPI-anchor; Lipoprotein; Membrane; KW Proteomics identification; Receptor; Reference proteome; Secreted; Signal; KW Transport. FT SIGNAL 1..16 FT CHAIN 17..230 FT /note="Folate receptor beta" FT /id="PRO_0000008806" FT PROPEP 231..255 FT /note="Removed in mature form" FT /id="PRO_0000008807" FT BINDING 97 FT /ligand="folate" FT /ligand_id="ChEBI:CHEBI:62501" FT /evidence="ECO:0007744|PDB:4KMZ" FT BINDING 101 FT /ligand="folate" FT /ligand_id="ChEBI:CHEBI:62501" FT /evidence="ECO:0007744|PDB:4KMZ" FT BINDING 118..122 FT /ligand="folate" FT /ligand_id="ChEBI:CHEBI:62501" FT /evidence="ECO:0007744|PDB:4KMZ" FT BINDING 151..156 FT /ligand="folate" FT /ligand_id="ChEBI:CHEBI:62501" FT /evidence="ECO:0007744|PDB:4KMZ" FT BINDING 190 FT /ligand="folate" FT /ligand_id="ChEBI:CHEBI:62501" FT /evidence="ECO:0007744|PDB:4KMZ" FT LIPID 230 FT /note="GPI-anchor amidated asparagine" FT /evidence="ECO:0000269|PubMed:7578066" FT CARBOHYD 115 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KN0" FT CARBOHYD 195 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMZ, ECO:0007744|PDB:4KN0, FT ECO:0007744|PDB:4KN1, ECO:0007744|PDB:4KN2" FT DISULFID 31..59 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 51..99 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 60..103 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 83..169 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 90..140 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 129..203 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 133..183 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT DISULFID 146..163 FT /evidence="ECO:0000269|PubMed:23934049, FT ECO:0007744|PDB:4KMY, ECO:0007744|PDB:4KMZ, FT ECO:0007744|PDB:4KN0, ECO:0007744|PDB:4KN1, FT ECO:0007744|PDB:4KN2" FT VARIANT 236 FT /note="H -> N (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036408" FT CONFLICT 103 FT /note="C -> V (in Ref. 6; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 111..112 FT /note="IQ -> VR (in Ref. 6; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 115 FT /note="N -> D (in Ref. 6; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 117 FT /note="S -> T (in Ref. 2; AAA35821, 3; AAA17370 and 6; AA FT sequence)" FT /evidence="ECO:0000305" FT CONFLICT 141 FT /note="H -> L (in Ref. 3; AAA17370)" FT /evidence="ECO:0000305" FT CONFLICT 244 FT /note="S -> R (in Ref. 3; AAA17370)" FT /evidence="ECO:0000305" FT HELIX 24..27 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 33..36 FT /evidence="ECO:0007829|PDB:4KMZ" FT HELIX 49..54 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 57..60 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 62..68 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 85..87 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 88..103 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 108..110 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 111..116 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 119..123 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 126..128 FT /evidence="ECO:0007829|PDB:4KN0" FT HELIX 130..140 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 150..152 FT /evidence="ECO:0007829|PDB:4KN0" FT HELIX 172..175 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 179..185 FT /evidence="ECO:0007829|PDB:4KMY" FT TURN 186..188 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 189..191 FT /evidence="ECO:0007829|PDB:4KMY" FT STRAND 200..204 FT /evidence="ECO:0007829|PDB:4KMY" FT HELIX 216..223 FT /evidence="ECO:0007829|PDB:4KMY" SQ SEQUENCE 255 AA; 29280 MW; F585715CF5631C98 CRC64; MVWKWMPLLL LLVCVATMCS AQDRTDLLNV CMDAKHHKTK PGPEDKLHDQ CSPWKKNACC TASTSQELHK DTSRLYNFNW DHCGKMEPAC KRHFIQDTCL YECSPNLGPW IQQVNQSWRK ERFLDVPLCK EDCQRWWEDC HTSHTCKSNW HRGWDWTSGV NKCPAGALCR TFESYFPTPA ALCEGLWSHS YKVSNYSRGS GRCIQMWFDS AQGNPNEEVA RFYAAAMHVN AGEMLHGTGG LLLSLALMLQ LWLLG //